Over the past several decades, progress in basic research has yielded a more
complete understanding of the pathophysiology of acute and chronic spinal
cord injury (SCI). This has led to clinical trials in a number of acute
treatments and the widespread application of one such treatment,
methylprednisolone, for human SCI. Research in chronic restorative therapies
is progressing and will hopefully yield beneficial treatments in the future.
Rehabilitation should progress to facilitate patient education and enable
incorporation of emerging therapies as they achieve clinical applicability.
Introduction. In the past, it was commonly believed that spinal cord injury
(SCI) was a condition not amenable to therapy intended to improve neurologic
function. Over the past several decades, however, progress in basic research
has yielded a more elaborate understanding of the underlying mechanisms of
tissue damage, healing processes, and the pathophysiology of neurologic
impairment after SCI. Progress in SCI research can be divided into several
broad categories based on the chronologic evolution of spinal cord
pathology. Acute therapies are directed at interrupting or interfering with
various steps of complex biochemical cascade that is set in motion by
traumatic contusion of the spinal cord. Chronic therapies are more directed
at stimulating repair or regrowth of chronically damaged neural elements.
Medical Treatment of Acute SCI.
Over the past several decades, animal experimentation in acute SCI has
yielded a more thorough understanding of the complex biochemical processes
that follow trauma to the spinal cord. While paralysis is typically
immediate in onset following injury, it is now known that a significant
proportion of long-term tissue damage is the result of secondary processes
that evolve hours after the injury. Contusion injury to the spinal cord
leads to progressive vascular and neuronal degeneration characterized by
loss of auto regulation, the intracellular accumulation of calcium ions, the
accumulation of vasoactive eicosanoids, excitotoxicity, oxygen free radical
accumulation, and lipid peroxidation of neuronal cell membranes. A better
understanding of these processes has led to the concept of a “window of
opportunity” wherein pharmacologic treatment aimed at one or more of these
pathophysiologic steps might limit the amount of tissue damage and thus
improve the chances for neurologic recovery.
Methylprednisolone is a glucocorticoid that has been used in the acute
treatment of SCI for decades. Based on the observation that the use of this
drug could produce improved function in individuals suffering from brain
edema, neurosurgeons had used methylprednisolone on an empiric basis in an
attempt to treat edema following spinal cord trauma. The first National
Acute Spinal Cord Injury Study (NASCIS I) studied doses commonly used in the
late 1970’s (100 to 1,000 mg/day) and found no evidence of treatment
effect when comparing the lower with the higher dose groups.1
Furthermore, it was thought that treatment for 10 days in the higher dose
group caused an increase in morbidity. At the time
of the publication of NASCIS I, it had also become apparent through further
animal research that the neuroprotective effect of methylprednisolone was
achieved through a more complex biochemical mechanism resulting in the
inhibition of lipid peroxidation through the “scavenging” of oxygen-free
radicals. To achieve this effect, much higher doses of methylprednisolone
would be required, leading to the NASCIS II, which was mounted in the late
1980’s and published in 1990.2 This important study was the first
randomized placebo-controlled large-scale trial of acute SCI treatment to
yield positive results. Patients whose methylprednisolone therapy was
initiated within 8 hours of injury showed improvements in motor and sensory
scores when compared with placebo counterparts at
6 weeks, 6 months, and 1 year after injury. Since the publication of NASCIS
II, the use
of high-dose methylprednisolone has become widespread in the United States
for the treatment of acute SCI.
Laboratory research had also suggested that a different class of chemicals,
gangliosides, could have beneficial effect in acute SCI by inhibiting the
cellular influx of calcium ions, reducing excitotoxicity, and potentiating
endogenous growth factors. A pilot study testing the efficacy of the
ganglioside GM-1 showed a promising effect when studied on a small group of
human subjects with acute SCI.3 The results of this study, which were
published in 1991, have led to a randomized, placebo-controlled, national
trial of high-dose methylprednisolone followed by 2 months of once daily
dosing of GM-1 or placebo.
Tirilazad mesylate is a 21-aminosteroid that possesses antioxidant
properties similar to methylprednisolone, but without the potential for
glucocorticoid side effects.4 A randomized placebo-controlled trial of this
medication following administration of high-dose methylprednisolone has also
been undertaken with the results yet to be released.
A number of other drugs have shown promise in animal SCI models including
opiate antagonists, inhibitors of excitotoxicity, antioxidants, and calcium
channel blockers.5 As animal research yields more information regarding the
effects of these drugs on SCI, we will hopefully see more therapies advance
to successful human trials.
Decades of basic and clinical research have finally come to fruition with
the 1990 publication of NASCIS II, which, for the first time, showed that
medical treatment of acute SCI could improve neurologic outcome. Several
other medications have shown promise and are in clinical trials yet to be
published. The success of this research has led to renewed hope for recovery
in the person with acute SCI.
Experimental Treatments of Chronic SCI. In contrast to the treatment dilemma
in acute SCI where therapy is directed at interrupting or inhibiting
progressive damage, the approach to chronic SCI is more concerned with
altering a chronic steady state, wherein the repair process has not produced
adequate recovery of function. The neurologic impairment caused by the
progressive damage of acute SCI results from the death of neurons,
interruption of axons, or failure of impulse conduction, typically due to
demyelinization. The pathology of chronic SCI is now understood to include
not only cavitation necrosis and the formation of glial scar, but also
significant demyelinization at the periphery
of the traumatic myelopathy.7 Inadequate recovery of function in the chronic
state is, therefore, likely due to inadequate repair of neural structures.
This is most commonly ascribed to the inability of neurons in the adult
mammalian central nervous system (CNS) to regenerate and to inadequate
remyelinization of demyelinated axons. In addition, since neurons do not
reproduce after the fetal state of development, replacement of dead neurons
cannot occur naturally. While a number of experimental therapies have shown
promise in animal models of chronic SCI, none have yet reached the stage of
development to enable widespread clinical application.
Perhaps the most widely studied potential chronic therapy involves tissue
implantation into the injured spinal cord.7 Peripheral nerve implants have
been proposed to provide a favorable environment for central neuron
regeneration. While initial animal experiments showed only histologic
evidence of central neuron regenerative growth, more recent studies have
also begun to show recovery of physiologic function and the formation of
functional synapses.8, 9 Schwann cells, the cellular component of peripheral
nerve felt to promote neuronal regeneration, have been implanted into
experimentally injured animal spinal cords. Cultured Schwann cells placed in
a semipermeable tube have been inserted into transected adult rat spinal
cords and were shown to promote significant axonal regeneration into the
graft. The regenerating axons were ensheathed and myelinated by Schwann
cells in the graft, but showed little capability to grow into host spinal
cord at the other side of the lesion and form functional synapses.10
Because of their growth properties,
their lack of immunoreactivity, and their limited promotion of glial scar,
fetal neuronal cell implants have also generated much scientific interest.
Fetal grafts implanted into the CNS not only survive, but also promote
connections with the host, both sending axons into the host and promoting
the growth of host axons into the graft.11 The abundance of such
interconnections would appear to be influenced by the maturity of the host,
with grafts placed into newborn animals producing the most extensive
interconnections of neurons while implants into more mature adult animals
result in relatively less elaborate connectivity.12 There is also evidence
that fetal implants into newborn animals are more likely to promote
extensive regeneration of host axons through the graft, thus acting not only
as a neurologic “relay,” but also as a “bridge.” Grafts into adult
animals would appear to predominantly act as “relays.”12 With recent
studies for the first time showing improvements in ambulatory behavior in
mammals with incomplete SCI after fetal cell grafting, the era of human
trials in tissue implantation may be approaching.13 Indeed, basic
researchers have begun the dialogue with clinicians to explore the possible
extension of this concept to human application.14 Some fetal transplants
have been performed into humans with SCI in Russia with very limited benefit
reported over a few spinal segments.14 While it is unclear how much benefit
may derive from such implants in humans, fetal grafts in Parkinsonism
indicate that such procedures can be relatively safe.15
Progress is also being made in further understanding the roles of trophic
factors and their counterpart inhibitory factors in recovery after SCI. The
combined application of specific nerve growth and antibodies to inhibitory
factors has been shown to produce long-distance regeneration of
corticospinal tract neurons in adult rats with SCI.16 More recently, young
adult rats with a partial interruption of the spinal cord showed recovery of
specific reflex and locomotor functions when treated with application
of antibodies to inhibitory factors.17
The potential benefit of combinations
of these therapies was documented in a recently reported study which
included both the implantation of peripheral nerve grafts and the use of a
growth factor in adult rats with experimental SCI.18 In this experiment,
which was the first to document behavioral improvement in an adult mammalian
species with a completely transected spinal cord, peripheral nerve bridges
were carefully routed from white matter to “permissive” grey matter and
stabilized in place with a fibrin glue containing acidic fibroblastic growth
factor. Animals which received both grafts and growth factor not only
exhibited histologic evidence of corticospinal tract regeneration, but also
regained functional posture, partial weight bearing, and stepping of the
hind limbs over a 6 month period.
In addition to animal studies of tissue implantation and growth-inhibitory
factors, the realm of chronic treatment has also seen new developments in
drug therapy and innovative rehabilitation research. 4-Aminopyridine is a
potassium channel blocker that has been found to produce a transient, modest
improvement in neurologic function in persons with spinal cord
demyelinization due to multiple sclerosis. With some of the neurologic
impairment in SCI due to focal demyelinization at the site of myelopathy,
application of this treatment is worthy of investigation. To date, several
small pilot studies on the effects of 4-Aminopyridine in chronic SCI have
shown temporary neurologic improvement in some individuals with incomplete
SCI, but no effect in more severely impaired individuals with motor complete
lesions.19 These preliminary reports have prompted interest in a more
extensive national collaborative trial to determine efficacy and safety.
Research in neurophysiology has also resulted in a greater understanding of
the nature of SCI neurologic impairment. Recent studies have, for the first
time, documented the presence of a central rhythm generator for locomotion
in man.20 Other workers have investigated the ability of the incompletely
injured spinal cord to modulate locomotor activity with peripheral sensory
inputs using treadmill training with partial body weight support.21 With
only an estimated 5% to 10% of descending axons required to produce
functional ambulation, this new appreciation of the spinal cord’s
functional capability will hopefully lead to innovative therapeutic
approaches to maximize the benefit of regenerative therapies.
Conclusion. While not yet ready for widespread clinical application,
restorative and regenerative therapies are beginning to show significant
promise in animal models of chronic SCI. The treatments under investigation
are not “cures” in the simple sense of the term, but rather biologic
treatments for chronic paralysis that will require growth and the
elaboration of neuronal interconnections to lay the foundation for
functional recovery. Neurologic improvement will manifest gradually over a
period of time and will likely benefit from rehabilitation to focus and
maximize functional gains. It is reasonable to hope the results of these
endeavors will provide improved quality of life for persons with SCI.
Rehabilitation clinicians should incorporate information about chronic SCI
research in patient education programs and look forward to incorporating
innovative treatments to promote functional recovery as they become
Reprinted with permission from Topics in Spinal Cord Injury Rehabilitation,
“Recovery of neurologic function in spinal cord injury: A review of new
and experimental therapies,” Daniel P Lammertse, MD, 1997;2(3):95-100.
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